Assay for lanthanum hydroxycarbonate

ABSTRACT

An assay for analytically determining the amount of an impurity in a solid sample is provided. This X-ray diffraction method preferably uses the Rietveld refinement.

1. FIELD OF THE INVENTION

This invention relates to the quantitative analysis of rare earthcompounds by X-ray diffraction. More particularly, the assay can be usedto determine lanthanum hydroxycarbonate impurities in a lanthanumcarbonate composition. The lanthanum hydroxycarbonate may also be madein a purified form for use as a standard.

2. BACKGROUND OF THE INVENTION

Lanthanum carbonate hydrate, which has been used to treathyperphosphatemia (see, e.g., U.S. Pat. No. 5,968,976) andhyperphosphatemia in patients with renal failure (see, e.g., JP1876384), is a molecule which is prone to decarboxylation under certainstressful conditions such as high heat and elevated humidity. Theseconditions may be present during the manufacture of lanthanum carbonatehydrate or during the storage of the unformulated or formulatedmaterial. The decarboxylation product is lanthanum hydroxycarbonate.

Certain forms of lanthanum carbonate have been used to treathyperphosphatemia in patients with renal failure (see, e.g., JP1876384). U.S. Pat. No. 5,968,976, owned by the assignee of the presentinvention, describes the preparation and use in a pharmaceuticalcomposition of certain hydrates of lanthanum carbonate for the treatmentof hyperphosphatemia.

It is a regulatory requirement that analytical methods be developed toquantify the amount of degradation products which may be present in apharmaceutical agent and a pharmaceutical product. Typically, this isdone using a chromatographic technique such as high performance liquidchromatography (HPLC), which requires dissolution of test samples in theappropriate solvent.

Both La₂(CO₃)₃ and LaCO₃OH are insoluble in water and standard organicsolvents. Either may be dissolved in acidic solution, but in doing so,reactions occur which form impurities in the sample. For example,dissolution of either La₂(CO₃)₃ or LaCO₃OH in aqueous hydrochloric acidresults in a solution of lanthanum chloride, (LaCl₃). Since bothmaterials give the same product after dissolution of a sample in acid,there is no way to distinguish La₂(CO₃)₃ from LaCO₃OH. Similarly, thesame salt is formed when either material is dissolved in other aqueousacids. Because of the insolubility of La₂(CO₃)₃ and LaCO₃OH in standardsolvents, and the fact that each substance reacts to form the samematerial in acidic solvents, chromatographic techniques such as HPLCcannot be used to develop quantitative methods to monitor the presenceof degradants.

It is conceivable that dissolution in aqueous acid and titration of theresulting solution for lanthanum content could be a technique used toquantify the amount of LaCO₃OH in La₂(CO₃)₃ hydrate. However, this isimpractical because the lanthanum content of both species is verysimilar. For example, LaCO₃OH contains 64.3% La, La₂(CO₃)₃ tetrahydratecontains 52.4% La, and a mixture of 1% LaCO₃OH in La₂(CO₃)₃ tetrahydratewould contain 52.5% La. Thus, one would be unable to distinguish purepharmaceutical agent from pharmaceutical agents containing, for example,1% degradant, which is an amount of degradant in excess of amountstypically allowed by regulations.

Various techniques might be used to develop quantitative analyticalmethods for analysis of solid mixtures. Examples of these techniquesinclude differential scanning calorimetry, infrared spectroscopy, Ramanspectroscopy, XRPD, solid-state nuclear magnetic resonance spectroscopy,and dynamic vapor sorption. The first criterion that must be met by ananalytical technique to render it usable for method development isspecificity. That is, the technique must be able to differentiate theanalyte from the matrix (i.e. LaCO₃OH from the pharmaceutical agentLa₂(CO₃)₃ hydrates and LaCO₃OH from La₂(CO₃)₃ hydrates when the sampleadditionally contains other excipients and/or carriers). However, mostof these techniques are not capable of differentiating LaCO₃OH fromLa₂(CO₃)₃ hydrates.

A technique capable of differentiating LaCO₃OH from La₂(CO₃)₃ hydratesis x-ray powder diffraction (XRPD). Normally XRPD is a technique whichis used to characterize materials and detect differences in crystalstructure (such as polymorphs). It is therefore usually used in theidentification of structures and is not normally used to quantifymaterials in the sense of an impurity or degradant assay.

Therefore, there is a need in the art to quantitatively determine thescope of material degradation and to quantifiably determine the level ofpurity of the degradation products of a rare earth compounds such asCaOHCO₃ compared to the rare earth compound itself (i.e., La₂(CO₃)₃).

3. SUMMARY OF THE INVENTION

In accordance with the present invention, provided herein is a method ofassaying the purity of a rare earth compound having at least one knownimpurity, wherein at least one of the salt or impurity is a compoundthat disassociates in aqueous media, comprising:

-   (i) obtaining an X-ray diffraction pattern of the salt;-   (ii) obtaining a plurality of reference samples containing the    impurity or impurities;-   (iii) obtaining a plurality of X-ray diffraction patterns of the    reference samples; and-   (iv) performing Rietveld analysis on the X-ray diffraction patterns    to obtain:

the detection limit, minimum quantitation limit (MQL), and/or upperanalytical limit from the reference samples and

the predicted impurity concentration value from the rare earth compoundpattern.

In one embodiment, the rare earth compound is a lanthanum carbonatecomposition and the known impurity is one or more polymorph of lanthanumhydroxycarbonate.

In another embodiment, the method further comprises (v) classifying thepredicted concentrations as:

below the detection limit,

between the detection limit and the MQL,

between the MQL and upper analytical limit, and

greater than the upper analytical limit;

-   (vi) for samples having a predicted concentration between the    detection limit and the MQL, performing a visual analysis of the    XRPD patterns; and-   (ix) optionally reporting purity or impurity level.

The present invention also provides a method of preparing a lanthanumcarbonate comprising:

-   (i) preparing a crude lanthanum carbonate;-   (ii) subjecting the crude lanthanum carbonate to a purity assay    comprising the steps:    -   (a) obtaining an X-ray diffraction pattern of the salt;    -   (b) obtaining a plurality of reference samples containing the        impurity or impurities;    -   (c) obtaining a plurality of X-ray diffraction patterns of the        reference samples; and    -   (d) performing Rietveld analysis on the X-ray diffraction        patterns to obtain:

the detection limit, minimum quantitation limit (MQL), and/or upperanalytical limit from the reference samples and

the predicted impurity concentration value from the rare earth compoundpattern,

-   (iii) when the lanthanum carbonate contains lanthanum    hydroxycarbonate above the limit of detection according to the assay    of (ii), purifying the lanthanum carbonate and repeating step (ii).

The present invention also provides a pharmaceutical compositioncomprising lanthanum hydroxycarbonate form (I) characterized by an X-raypowder diffraction pattern having reflections at approximately 17.7,24.4, and 30.3° two theta, wherein the lanthanum hydroxycarbonatecontent of the composition comprises at least 96% lanthanumhydroxycarbonate form (I). Preferably, the two theta values will bewithin ±0.2° of the listed values, and more preferably, the two thetavalues will be within ±0.1° of the listed values. More preferably, thecomposition comprises at least 98% lanthanum hydroxycarbonate form (I),and even more preferably, the composition comprise at least 99%lanthanum hydroxycarbonate form (I).

The above features and many other attendant advantages of the inventionwill be better understood by reference to the following detaileddescription.

4. BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 is an XRPD (x-ray powder diffraction) pattern of La₂(CO₃)₃.4H₂O.

FIG. 2 is an XRPD pattern of La₂(CO₃)₃.8H₂O.

FIG. 3 is an XRPD pattern of La(CO₃)OH form (II).

FIG. 4 is an XRPD pattern of La(CO₃)OH form (I).

FIG. 5 is an overlay of 4 XRPD patterns of La₂(CO₃)₃.4H₂O (top pattern),La₂(CO₃)₃.8H₂O, La(CO₃)OH 3 form (I) and La(CO₃)OH form (II) (bottompattern).

FIG. 6 depicts the actual concentration of La(CO₃)OH form (I) standardscompared to the concentration of La(CO₃)OH form (I) as calculated by theRietveld method and a linear regression.

FIG. 7 depicts the actual concentration of La(CO₃)OH form (II) standardscompared to the concentration of La(CO₃)OH form (II) as calculated bythe Rietveld method and a linear regression.

FIG. 8 is an XRD Overlay of four samples containing La₂(CO₃)₃.4H₂O andLa(CO₃)OH and a La(CO₃)OH standard.

FIG. 9 is an XRD Overlay of four samples containing La₂(CO₃)₃.4H₂O andLa(CO₃)OH and a La(CO₃)OH standard.

5. DETAILED DESCRIPTION OF THE INVENTION

5.1. General Definitions

As used herein, the terms “about” or “approximately” mean within anacceptable range for the particular parameter specified as determined byone of ordinary skill in the art, which will depend in part on how thevalue is measured or determined, e.g., the limitations of the samplepreparation and measurement system. Examples of such limitations includepreparing the sample in a wet versus a dry environment, differentinstruments, variations in sample height, and differing requirements insignal-to-noise ratios. For example, “about” can mean a range of up to20% of a given value, and more preferably means a range of up to 10%.Alternatively, particularly with respect to biological systems orprocesses, the term can mean within an order of magnitude, preferablywithin 5-fold, and more preferably within 2-fold, of a value.

“Lanthanum carbonate” as used herein encompasses all polymorphs ofhydrated forms of lanthanum carbonate and of anhydrous lanthanumcarbonate.

The term “hydrated lanthanum carbonate” refers to lanthanum carbonatehaving water content approximately equivalent to 4-5 moles of water.

“Lanthanum hydroxycarbonate” as used herein encompasses all polymorphsof lanthanum hydroxycarbonate, including form (I) and form (II). Theterm HC(I) refers to lanthanum hydroxycarbonate polymorphic form (I) asdescribed by the XRD pattern in FIG. 3. The term HC(II) refers tolanthanum hydroxycarbonate polymorphic form (II) as described by the XRDpattern in FIG. 4.

The phrase “rare earth compound” as used herein refers to a compoundcontaining at least one rare earth element of the lanthamide series,yttrium, scandium, and thorium. The lanthamide series comprises cerium,praseodymium, neodymium, samarium, europium, gadolinium, terbium,dysprosium, holmium, erbium, thulium, ytterbium, and lutetium. Each ofthese elements closely resemble lanthanum in their chemical and physicalproperties, each having similar so that any given compound of the rareearths is likely to crystallize with the same structure as any otherrare earth. Similar salts of these metals will have common propertiesincluding reacting with water to liberate hydrogen, binding to water,and acting as strong reducing agents.

“Percent” or “%” as used herein refers to the percentage by weight ofthe total composition unless otherwise noted.

The term “substantially pure,” when referring to either lanthanumcarbonate or lanthanum hydroxycarbonate, refers to the lanthanumcompound having about 90% purity or greater, on an anhydrous basis.Preferably, the purity is about 95% or greater; more preferably, thepurity is 98% or greater; even more preferably, the purity is 99% orgreater. It is preferred that the purity is 99.2% or greater; morepreferably, the purity is 99.4% or greater; even more preferably, thepurity is 99.6%; even more preferably, the purity is 99.8% or greater;and even more preferably, the purity is 99.9% or greater.

The term “salt” is used herein refers to the ionic product of a reactionbetween a metallic oxide and an acid. The salts useful in the presentinvention are salts of rare earth elements such as lanthanum.

The term “lanthanum salt” as used herein refers to lanthanum bound to anegatively charged anion to create a neutral species. Examples ofhydrolysable lanthanum salts include, but are not limited to lanthanummethoxyethoxide, lanthanum acetate, lanthanum acetylacetonate, lanthanumoxalate, and hydrates thereof . . . Preferably, the hydrolzablelanthanum salt is a lanthanum (III) salt.

The phrase “a compound that disassociates in aqueous media” as usedherein means that at least some of the compound separates into two ormore components such as La₂(CO₃)₃ separating into La³⁺ and CO₃ ²⁻. Thisdisassociation may be induced by an acidic environment (e.g., aqueousHCl) and may be followed by the formation of salts such as LaCl₃.

The phrases “Rietveld analysis” and “Rietveld method” as used hereinmean the data is analyzed using the constrained, full pattern analyticalmodel first developed by Rietveld (Acta. Crystallogr., 22, 151-2, 1967,and J. Appl. Crystallogr., 2, 65-71, 1969). Constrained analysis meansthat the analytical model is limited, or constrained, using one or moreparameters obtained from chemical or other information about the sample.In particular, the assay for the impurity lanthanum hydroxycarbonate ina lanthanum carbonate sample may be constrained using the knowledge ofthe crystal structure of the components in the sample: lanthanumcarbonate tetrahydrate, other lanthanum carbonate hydrates, lanthanumhydroxycarbonate form (I) and lanthanum hydroxycarbonate form (II). Afull-pattern analysis is one in which the full XRD pattern in analyzedinstead of only the more intense peaks. The full pattern encompasses arange of two-theta values, and may include, for example, the range from9 to 40 °2θ, or from 10 to 35 °2θ. Full-pattern analysis can be used toprovide greater accuracy and precision to the quantitative analysis thana peak-intensity based method. The phrases “Rietveld analysis” and“Rietveld method” also include analyses using a modification of theRietveld method, such as those described by Bish, D. L. and Howard, S.A. 1988 (J. Appl. Crystallography, 21, 86-91). Other modifications ofthe Rietveld method are also contemplated as within the scope of theRietveld analysis.

5.2. Lanthanum Carbonate and Lanthanum Hydroxycarbonate

Lanthanum carbonate has the general formula La₂(CO₃)₃.xH₂O, wherein xhas a value from 0 to 10. A common form of the hydrate has an average xvalue of about between 3 and 5. The hydration level of the lanthanumcompound can be measured by methods well known in the art, such asthermo gravimetric analysis (TGA) or x-ray powder diffraction (XRPD).

Lanthanum carbonate has a tendency to degrade via decarboxylation tolanthanum hydroxycarbonate as shown:La₂(CO₃)₃ +nH₂O→2LaOHCO₃+CO₂+(n−1)H₂OSubjecting La₂(CO₃)₃ hydrate to hydrothermal conditions (water at hightemperature and pressure) affords lanthanum hydroxycarbonate (LaCO₃OH).(Aumont, R.; Genet, F.; Passaret, M.; Toudic, Y. C.R. Acad. Sci. ParisSer. C 1971, 272, 314; Christensen, A. N. Acta Chem. Scand. 1973, 27,2973; Haschke, J. M. J. Solid State Chem. 1975, 12, 115). The samereaction occurs under relatively mild conditions such as heating a waterslurry of La₂(CO₃)₃ hydrate under ambient pressure at 77° C. for 20hours followed by 97° C. for 1.5 hours (Sun, J.; Kyotani, T.; Tomita, A.J Solid State Chem. 1986, 65, 94). It is known that LaCO₃OH exists intwo polymorphic forms (I) and (II) (id.)

This process is accelerated in the presence of moisture or heat andappears to be self-catalyzing. Hence, even a very small amount oflanthanum hydroxycarbonate in lanthanum carbonate formulations causesrapid and excessive degradation.

Further, conditions sufficient to bring about decarboxylation of thesematerials may be present during their manufacture as well as duringstorage in a formulated or unformulated state. Thus, there is apossibility that La₂(CO₃)₃ hydrate used as an active pharmaceuticalingredient would contain the degradation product LaCO₃OH, either aspolymorph (I) or polymorph (II).

Lanthanum carbonate tetrahydrate and octahydrate can be made by methodsknown in the art including the method described in U.S. Pat. No.5,968,976.

The degradation of lanthanum carbonate into lanthanum hydroxycarbonatecan be observed by examining an XRPD pattern of a potentially degradedlanthanum carbonate sample. The presence of observable peakscorresponding to lanthanum hydroxycarbonate in the sample patternindicates degradation whereas the absence of observable peaks indicatesno detectable degradation.

Generally, lanthanum hydroxycarbonate may be synthesized by methodsknown in to those skilled in the art including, (I) from hydratedlanthanum(III) carbonate under hydrothermal conditions as disclosed inHaschke, J., J. Solid State Chemistry, 12 (1975) 115-121; (2) fromLaBr(OH)₂ treated with carbon dioxide or from hydrolysis of lanthanumcarbonate as disclosed in Sun, J.; Kyotani, T.; Tomita, A. J. SolidState Chem., 65 (1986) 94; (3) the treatment of lanthanum(III) nitratewith urea or thiourea as disclosed in Han et al. Inorganic ChemistryCommunications, 6 (2003) 117-1121; (4) the treatment of lanthanum(III)chloride with urea or thiourea as disclosed in Han et al. Journal ofSolid State Chemistry, 177 (2004) 3709-3714; (5) the treatment oflanthanum(III) chloride with trifluoroacetic acid as disclosed inWakita, H et al., Bulletin of the Chemical Society of Japan, 52 (1979)428-432; or (6) the treatment of lanthanum(III) chloride with sodiumcarbonate as disclosed in Nagashima, K et al. Bulletin of the ChemicalSociety of Japan, 46 (1973) 152-156.

5.3. Rare Earth Compounds

Other rare earth compounds will degrade or react to form impurities inthe product sample. For example, compounds such as lanthanum citrate,acetate, lactate methoxyethoxide, acetylacetonate, oxalate, and hydratesthereof may be analyzed in the same manner as disclosed herein for thelanthanum carbonate.

For example, lanthanum acetate will degrade to form a hydroxy derivative(i.e., La(OAc)_(3-x)(AcAc)_(x), will hydrolyzed intoLa(AcAc)_(3-x)(OH)_(x) (Yin, M Z et al., J Zhejiang Univ Sci. 2004 5(6),696-8)). It is contemplated that concentrations of lanthanumhydroxyacetate impurities can be determined in the same or similarmanner as described herein for lanthanum hydroxycarbonate by replacingthe hydroxycarbonate standards with hydroxyacetate standards andmodifying the parameters used in the Rietveld analysis for the crystalof the hydroxyacetate isoform(s).

Similarly, lanthanum citrate (i.e., La(Hcit)(H₂O)]_(n) where (Hcit³⁻) isC(OH)(COO⁻)(CH₂COO⁻)₂) can hydrolyze to form a hydroxy derivative.Lanthamide citrate has a structure comprising chains of La(III) cationsbridged by O—C—O groups with pendant Hcit anions; the Hcit ligand isinvolved in six La—O bonds to five different La centers. (Baggio R,Perec M. Inorg Chem. 2004; 43(22), 6965-8). It is contemplated thatconcentrations of lanthanum hydroxycitrate impurities can be determinedin the same or similar manner as described herein for lanthanumhydroxycarbonate by replacing the hydroxycarbonate standards withhydroxycitrate standards and modifying the parameters used in theRietveld analysis for the crystal of the hydroxycitrate isoform(s).

Other rare earth salts will degrade similarly to lanthanum salts sincethese elements closely resemble lanthanum in their chemical and physicalproperties. Therefore, some degradation impurities of other rare earthsalts may also be analyzed using the XRD analysis method of the presentinvention for other rare earth metal salts. To determine whether thedegradation product and the compound such as those discussed above canbe analyzed by the method of the present invention, an XRD of both thecompound and the degradation product must be obtained and the parametersused in the Rietveld analysis for the crystal structures must beobtained as appropriate for the compounds used, as described herein forthe parameters used for analysis of lanthanum hydroxycarbonate. The twospectra must differ in at least one structural feature. Preferably, thisfeature will comprise a number of unique positions (2 theta) andintensities.

5.4. Preparation of Substantially Pure Compounds

To prepare standards for the assay of the present invention,substantially pure forms of each of the compounds and polymorphs must bemade. These samples are then used to prepare reference samplescontaining a varying amount of each of the different components of thesample. In one embodiment, the reference samples will span a range from0-50% of the impurity (each polymorph if more than one polymorph is inthe sample), or more preferably 0-30%. In another embodiment, thereference samples span only a narrow range of, for example, 0-10% of theimpurity. The standards are used to calibrate the scale factors in theanalytical model described herein.

For the more stable of the two lanthanum hydroxycarbonate polymorphs,form (II), the production of a substantially pure sample is accomplishedby the methods known in the art. However, the production of polymorph(I) is not as simple since this compound is not soluble in many of theorganic solutions commonly used for recrystallizing and formingdifferent polymorphs.

Factors important to the synthesis of hydroxycarbonate polymorph (I)include temperature, humidity, the presence of unreacted La(OH)₃,reaction scale, and the particle size of the starting material.

An attempt was made to convert polymorph (II) to polymorph (I) byheating in water for an extended period of time. No evidence ofconversion was seen after 18 days at 90-100° C. Experiments in whichLa₂(CO₃)₃.8H₂O was treated with La(OH)₃ in water afforded either amixture of LaCO₃OH polymorphs (I) and (II) or LaCO₃OH polymorph (II) andunreacted La₂(CO₃)₃.8H₂O.

Decarboxylation of either La₂(CO₃)₃.4H₂O or La₂(CO₃)₃.8H₂O in thepresence of water alone afforded either wholly or predominantlypolymorph form (II). The presence of hydroxide ion duringdecarboxylation of La₂(CO₃)₃.8H₂O can favor production of LaCO₃OHpolymorph (I). However, production of form (I) with additional OH— isinconsistent.

It was also noted that decarboxylation of La₂(CO₃)₃.8H₂O under a carbondioxide atmosphere gave some polymorph (I). This would be expected ifthe carbon dioxide inhibited the reaction giving polymorph (II) andallowed the reaction giving polymorph (I) to occur at reflux.

Ammonium carbonate was therefore used as an additive to liberate carbondioxide as it was heated, providing a constant source of the inhibitorof the reaction leading to polymorph (II). Indeed, the major product inmost of these reactions was polymorph (I). By using an amount ofammonium carbonate which was approximately 25% of the weight ofLa₂(CO₃)₃.8H₂O, the formation of polymorph (II) was completelysuppressed and the product was pure polymorph (I).

This substantially pure form (I) can then be used to create a standardused in the Rietveld analysis of the content of LaCO₃OH form (I) in asample. Additionally, this polymorph is useful as a pharmaceuticalagent. Similar to the carboxylated salt, LaCO₃OH form (I) can be used totreat hyperphosphatemia. The substantially pure compound can optionallybe mixed with one or more pharmaceutically acceptable carrier orexcipient and used in the manner described for La₂(CO₃)₃ hydrate.

Similarly, substantially pure form (II) can be used as both a standardused for the Rietveld analysis to determine the content of LaCO₃OH form(II) in a sample and as a pharmaceutical agent, such as an agent for thetreatment of hyperphosphatemia. This isoform can be administered to apatient as an active agent or in a pharmaceutical composition withoutalso administering form (I) or other impurities to the patient as well.In addition, a pharmaceutical agent containing a known mixture of form(I) and form (II) LaCO₃OH can be formed and used for treatinghyperphosphatemia.

5.5. Analysis Model

Quantitative analytical methods were developed for pharmaceutical agentsand drug products based on XRPD measurements. The method of datamodeling initially selected was a chemometric one called partial leastsquares (PLS) analysis. PLS is a statistical approach that results in anequation (model) that describes the correlation between composition andmultiple measured variables. The PLS algorithm examines user-specifiedregions of the calibration data to determine which areas are varyingstatistically as a function of component concentration. The number ofvariables can be large, so whole-pattern models can be generated thatutilize all measured data. For results from a model of this type to beaccurate, the data obtained from a test sample need to ‘fit’ the model.Any data obtained that are outside of the range allowed for those databy the model may cause inaccuracy. Goodness-of-fit metrics like thespectral F ratio provide a measure of how well measured data fit themodel. PLS is a useful approach when the components to be monitoredexperience severe overlap with other components in the mixture, when thecorrelation between concentration and absorbance is very complex, orwhen additional components whose concentrations are unknown may bepresent in the sample mixture. Since PLS is a statistical analysistechnique, a large number of standards are needed in order to correlatethe analytical data with concentration.

As samples were being analyzed using XRPD data with a PLS model, thegoodness-of-fit metric was found to be outside the established thresholdin some cases. Investigation revealed that the XRPD patterns weresomewhat different in the problem samples compared to the patterns ofthe materials used to generate the PLS model. An investigation of thepattern differences was undertaken, necessitating an understanding ofthe crystal structures of the component substances of the mixtures.

The structures of La₂(CO₃)₃ tetrahydrate, LaCO₃OH polymorph (I), andLaCO₃OH polymorph (II) were not available in the literature. The presentinvention provides structural models of the latter three materials basedon XRPD data and the structures of similar materials in the literature.It was found that La₂(CO₃)₃ tetrahydrate is a layered structure in whichthe layers consist of La₂(CO₃)₃ species with water bound between thelayers. On the other hand, both polymorphs of LaCO₃OH are stronglybonded in all three dimensions. The result is that La₂(CO₃)₃tetrahydrate breathes with increasing or decreasing amounts of water;the layers are further apart with increasing amounts of water. Thisbreathing affects both the shape and intensity of the main reflectionspecific for tetrahydrate in the XRPD pattern. Because PLS methods areextremely sensitive to these sorts of changes, the initial PLS modelscreated using one type of tetrahydrate material could not be used topredict mixture concentrations that contained a different tetrahydratematerial. These differences in the tetrahydrate materials becameapparent when samples were submitted for analysis via the PLS methodsand the unexpected results were obtained. The differences observed inthe XRPD patterns of samples being analyzed were consistent with smallchanges in layer separation expected with changes in the amount ofcontained water. Note that the changes in the amount of water were notsufficient to render the La₂(CO₃)₃ tetrahydrate samples out ofspecification as far as water content. The crystal structure ofLa₂(CO₃)₃ octahydrate is known, (Shinn, D. B.; Eick, H. A. Inorg. Chem.1968, 7, 1340), and data from this structure can be used in the Rietveldanalysis.

It was found that the problem exhibited by PLS data modeling could beovercome using another full-spectrum model, Rietveld analysis. Thismethodology was originally proposed by H. M. Rietveld for determiningstructural parameters from XRPD data. (Rietveld, H. M. J. Appl.Crystallogr. 1969, 2, 65). Three dimensional structures of crystallinematerials are typically deduced from x-ray studies of single crystals,but when single crystals are not available, the Rietveld method can beused to deduce the structures from XRPD data and thereby used toconstrain the data. By substituting Rietveld analysis for PLS analysis,the method was made robust relative to the differences observed in XRPDdata sample-to-sample. The Rietveld method varies structural factorsderived from the crystal structures in order to generate the best fit ofmeasured and calculated XRPD patterns. Since the structure of La₂(CO₃)₃tetrahydrate does not change sample-to-sample, but only expands orcontracts based on water content, Rietveld treatment can model the layerseparation differences based on the underlying structure.

The Rietveld method then minimizes the least square residual:$R = {\sum\limits_{j}\quad{w_{j}{{I_{j{(o)}} - I_{j{(c)}}}}^{2}}}$

where I_(j(0)) and I_(j(c)) are the intensity observed and intensitycalculated by the Rietveld refinement, respectively, at the jth step inthe data, and wj is the weight.

The refinement iteratively fits to the data by modifying the structureand instrument parameters.

This method is also advantageous because it uses the whole XRD patterninstead of a number of selected peaks. This, although increasing thecalculation time, provides for much greater accuracy and precision ofthe fit.

Further information on this method can be found in Rietveld, H. M. “LineProfiles of Neutron Powder-diffraction Peaks for Structure Refinement.”Acta. Crystallogr., 22, 151-2, 1967, and Rietveld, H. M., “A ProfileRefinement Method for Nuclear and Magnetic Structures.” J. Appl.Crystallogr., 2, 65-71, 1969, each of which are herein incorporated byreference.

In a preferred embodiment, the results returned from the Rietveldanalysis are based on the following criteria: Predicted ConcentrationReported Value <LOD “non-detectable, complies” LOD - MQL user inputneeded MQL -upper analytical report concentration, “does not comply”limit >upper analytical limit >upper analytical limit, “does not comply”where LOD is the limit of detection, or detection limit, given at a 99%confidence limit. MQL is the minimum quantitation limit, which may alsobe defined as the limit of quantitation (LOQ) is the limit at whichaccurate quantitation is possible. MQL may be expressed as 10(σ/S),where σ is the standard deviation of the observed response of samplesfree of analyte and S is the slope of the response curve.

If the predicted concentration is between the LOD and the MQL, then theindividual XRDP patterns should be co-added (when more than one XRDP wasobtained) and visually examine for the presence of hydroxycarbonateversus the hydroxycarbonate reference patterns. Report either “DetectedRietveld, none detected visual-complies” or “Detected Rietveld andvisual—does not comply”.

The assay of the present invention preferably follows the analyticalguidelines provided by the International Committee on Harmonization(1CH) document (November 1996) “Guidance for Industry, Q2B Validation ofAnalytical Procedures: Methodology.” These guidelines includelimitations on specificity, linearity and range, precision, detectionlimits, minimum quantitation limits, accuracy of the validationstandards, system suitability, and ruggedness.

5.5 Excipients

The assay of the present invention is particularly useful since it isable to analyze impurity content of an active agent in the presence ofexcipients. As discussed below, a tablet form of lanthanum carbonate canbe tested for the relative weight percent of the hydroxycarbonatepolymorphs. These excipients do not significantly interfere with theanalytical measurements.

6. EXAMPLES Example 6.1 Preparation of Pure Hydroxycarbonate Polymorph(II)

The starting material, La₂(CO₃)₃.4H₂O, was provided by ShirePharmaceutical and was analyzed by XRPD to confirm its identity. Amixture of about 1500 g (2.8 mol) of La₂(CO₃)₃.4H₂O and 10 liters ofwater was heated to approximately 60° C. for approximately 2 h. A samplewas removed and analyzed by XRPD. The mixture was heated toapproximately 70° C. for approximately 17 h. A sample was removed andanalyzed by XRPD. The mixture was heated to approximately 80° C. forapproximately 7 h. A sample was removed and analyzed by XRPD. Themixture was heated to approximately 90° C. for approximately 13 h. Asample was removed, analyzed by XRPD, and found to be completelyhydroxycarbonate polymorph (II). The mixture was allowed to cool toambient temperature and filtered. The solid was dried under vacuum pumppressure for approximately three days to give 1151 g of hydroxycarbonatepolymorph (II).

A portion of the sample was analyzed by XRPD. Another portion wasanalyzed by an ICP metal scan (Quantitative Technologies Inc.) to give220 ppm K, and less than 20 ppm for each of the other quantifiable atomstested. This sample was assayed by titration and Karl Fischer analysisfor water content. The sample contained 96.3% lanthanum, 93.6% hydroxycarbonate, and a water content of <1%.

Example 6.2 Preparation of Pure Hydroxycarbonate Polymorph (I)

A mixture of 15.0 g of La₂O₃, 24.7 mL of 37.7% hydrochloric acid, and 42mL of water was cooled to ice bath temperature and filtered. To the coldfiltrate was added, dropwise, a solution of 15.7 g of ammonium carbonatein 70 mL of water. The resulting slurry was allowed to warm to ambienttemperature and stirred overnight. The solids were recovered by vacuumfiltration, washed with three 50-mL portions of water, allowed to dry inthe air, and added to a solution of 6.31 g of ammonium carbonate in 107mL of water. The resulting slurry was heated to reflux for approximately24 h. A portion of solid was removed, analyzed by XRPD, and found tocontain only hydroxycarbonate polymorph (I). The reaction slurry wasvacuum filtered and the solids were allowed to dry in the air, washedwith 76 mL of water, recovered by vacuum filtration, and again allowedto dry in the air to give 17.7 g of hydroxycarbonate polymorph (I).

A portion of the sample was analyzed by XRPD. Another portion wasanalyzed by an ICP metal scan (Quantitative Technologies Inc.) to give214 ppm K, 192 ppm Si, and less than 20 ppm for each of the otherquantifiable atoms tested. A 1.3 g portion of this sample was assayed bytitration to give 94.6% lanthanum, 94.0% hydroxy carbonate.

Example 6.3 XRD Using Visual and PLS Models

Lanthanum hydroxycarbonate was first analyzed using a visual and partialleast squares method using the XRD data. The analytical method forlanthanum hydroxycarbonate in lanthanum carbonate was done as a 2-stateprocess: a visual one and a quantitative one. Stage 1 was the visualevaluation of the XRD spectra to determine if any LHC was visible. Thevisual technique was used because this gave the lowest limit ofdetection (LOD) possible, certainly lower than a typical calculationmodeling method such as PLS. However PLS modeling and analysis was usedfor the second stage to provide quantitation of the impurities. Thisgives LOD and limit of quantitation (LOQ) as follows:

Lanthanum hydroxycarbonate polymorph (I): LOD 1.7% visual LOQ 2% PLS

Lanthanum hydroxycarbonate polymorph (II): LOD 0.3% visual LOQ 3.4% PLS

Similarly, tablet samples were prepared and the LOD for each polymorphwas estimated at 0.5% w/w of tablet weight (actually 0.39 and 0.57% forpolymorph (I) and (II) respectively). At 0.5% of tablet weight, thisequates to 9 mg each of lanthanum hydroxycarbonate polymorph (I) and(II) in an 1800 mg tablet containing 477 mg of lanthanum carbonatetetrahydrate=i.e. around 2% for each polymorph when expressed aslanthanum hydroxycarbonate % w/w of ingoing lanthanum carbonatetetrahydrate).

Lanthanum carbonate quantitative XRD results of the tablets by PLSmodeling was not able to detect LA(CO₃)OH polymorph-I (<1.7% w/w), anddetected polymorph (II) in the 4 tablets at <3.4%, 13.8%, 20.2%, and<3.4% (w/w).

Example 6.4 XRD Using Rietveld Analysis

X-ray powder diffraction (XRPD) was used to determine the lanthanumhydroxycarbonate (I and II) concentrations in lanthanum carbonatetetrahydrate. Quantitation was based on Rietveld modeling andcalibration against a set of 28 standards. Analytical figures-of-merit(accuracy, precision, robustness) were derived from an independent dataset. Reported concentrations are weight percent relative to the totaldrug substance. This method assumes that lanthanum carbonatetetrahydrate was the major component of the active pharmaceuticalingredient, and that the only other species present in the lanthanumcarbonate were lanthanum carbonate octahydrate and hydroxycarbonate (Iand II).

A. Materials

The materials used to generate calibration and validation samples weresieved using a 106 μm sieve. The hydrates of La₂(CO₃)₃ were preparedusing methods known in the art such as those described in U.S. Pat. No.5,968,976. The pure hydroxycarbonate compounds used to make thecalibration and validation samples are made in Examples 6.1 and 6.2. Allsample mixtures were prepared by geometric mixing to ensure samplehomogeneity. The X-ray structure of these samples are shown in FIGS.1-4. Twenty-eight samples as shown below were made containing two ormore of La₂(CO₃)₃ tetrahydrate, La₂(CO₃)₃ octahydrate, La(CO₃)OHpolymorph (I) and La(CO₃)OH polymorph (II). Corrected % corrected %Sample tetrahydrate % octahydrate % HC(I) HC(II) 1 93.648 2.622 2.5351.195 2 93.640 2.548 0 3.812 3 93.801 0 5.0023 1.197 4 93.785 5.0185 01.197 5 93.750 0 2.494 3.756 6 93.649 1.738 1.741 2.872 7 93.601 0 06.391 8 89.311 4.714 0 5.975 9 88.915 9.9502 0 1.135 10 88.861 0 4.8366.303 11 88.813 0 10.054 1.133 12 88.777 5.054 5.036 1.133 13 88.686 0 011.314 14 87.987 3.51 3.68 4.823 15 79.247 0 9.859 10.894 16 79.1059.910 9.976 1.009 17 79.042 0 0 20.958 18 78.913 0 20.08 1.007 19 78.70620.29 0 1.004 20 78.573 6.655 6.955 7.817 21 78.469 10.32 0 11.211 2269.473 14.70 14.94 0.887 23 69.181 0 29.936 0.883 24 69.079 14.90 016.021 25 69.059 0 15.09 15.851 26 68.992 0 0 31.008 27 68.964 30.156 00.880 28 67.831 9.743 10.42 12.006B. X-ray Powder Diffraction Analysis

XRPD analyses were performed using a Shimadzu XRD-6000 X-ray powderdiffractometer using Cu Ka radiation. The instrument was equipped with along fine focus X-ray tube. The tube voltage and amperage were set to 40kV and 40 mA, respectively. The divergence and scattering slits were setat 1° and the receiving slit was set at 0.15 mm. Diffracted radiationwas detected by a NaI scintillation detector. A theta-two thetacontinuous scan at 1°/min (1.2 sec/0.02° step) from 9 to 40 °2θ wasused, and the sample was rotated at 50 rpm during analysis. A siliconstandard was analyzed to check the instrument alignment. Data werecollected and analyzed using XRD-6000 v. 4.1. Samples were analyzed in aback-fill aluminum holder.

Three individual diffractograms were collected for each sample. Sampleswere either mixed and repacked into the sample holders between each ofthe individual runs, or separate aliquots were subsampled from the bulk.The experimental parameters were: continuous scan, 9-40 °2θ, 1°/minscan, 0.02° step, rotate at 50 rpm divergence slit=scatter slit=to,receiving slit=0.15 mm. After obtaining the spectra, the files wereconverted to ascii-format and the individual diffractograms were x-axisshifted as necessary using the −18.4° reflection of lanthanum carbonateXRPD pattern as the shift reference (GRAMS) and export the files to theformat used for the full-pattern analysis (pm format for the MaudRietveld Analysis software).

C. Data Analysis

XRPD diffractograms were converted to ASCII format using Shimadzusoftware (Shimadzu XRD-6000 v4.1) or File-Monkey (v1.1), and convertedto .spc file format using GRAMS software (v6.0). The diffractograms wereexamined for two-theta correspondence versus a standard pattern and ifnecessary, the patterns were x-axis shifted using the −18.4° reflectionas the shift reference. The diffractograms were then converted to prnformat using GRAMS, and Rietveld analysis was performed using Maudsoftware (Material Analysis Using Diffraction;www.ing.unitn.it/luttero/maud/, v1.998).

Rietveld results from the triplicate determinations of each sample wereaveraged, and calibration equations were developed by regressing theactual analyte content of the standards versus the Rietveld results.

The percent recovery for the validation samples was calculated using thefollowing equation:% Recovery=(Predicted % Analyze)/(Actual % Analyte)×100%

A pooled standard deviation was calculated from the results of replicateanalyses of multiple samples using the following equation:Pooled standard deviation=(SStotaUdf)^(1/2),where: SStotal=sum of squares of deviations from the mean for allsamplesdf=degrees of freedom (total number of replicates−total number ofsamples)D. Specificity

XRPD patterns of the lanthanum carbonate tetrahydrate, octahydrate, andhydroxycarbonate (I), and hydroxycarbonate (II) used as components forcalibration and validation mixtures are shown in FIGS. 1-4. Visualexamination of the XRPD overlay of the four components (FIG. 5) showsregions in which any single component can be clearly differentiated fromthe others. XRPD analysis demonstrates specificity for these componentsand is therefore a suitable technique for quantitation.

E. Linearity and Range

Rietveld results for the 28 mixtures used as calibration standards andthe average values for the triplicate determinations are: RietveldRietveld Actual Avg % Actual Avg % Sample % HC(I) HC(I) Error % HC(II)HC(II) Error 1 2.54 2.36 0.03 1.20 1.58 0.15 2 0.00 0.52 0.27 3.81 3.640.03 3 5.00 4.35 0.43 1.20 1.54 0.12 4 0.00 0.35 0.12 1.20 1.54 0.12 52.49 2.40 0.01 3.76 3.59 0.03 6 1.74 1.60 0.02 2.87 2.98 0.01 7 0.000.41 0.17 6.39 5.58 0.66 8 0.00 0.35 0.12 5.97 5.54 0.19 9 0.00 0.150.02 1.13 1.35 0.05 10 4.84 4.30 0.29 6.30 5.76 0.30 11 10.05 8.23 3.311.13 1.57 0.19 12 5.04 4.19 0.72 1.13 1.53 0.16 13 0.00 0.57 0.32 11.319.66 2.75 14 3.68 3.45 0.05 4.82 4.52 0.09 15 9.86 8.62 1.54 10.89 8.963.73 16 9.98 8.64 1.78 1.01 1.38 0.13 17 0.00 0.54 0.30 20.96 17.97 8.9318 20.08 16.28 14.44 1.01 1.55 0.29 19 0.00 0.10 0.01 1.00 1.22 0.05 206.96 6.26 0.48 7.82 6.59 1.50 21 0.00 0.30 0.09 11.21 9.84 1.87 22 14.9412.54 5.79 0.89 1.13 0.06 23 29.94 24.56 28.90 0.88 1.38 0.25 24 0.000.39 0.15 16.02 14.10 3.70 25 15.09 13.3 2.91 15.85 11.97 15.04 26 0.000.56 0.31 31.01 26.59 19.52 27 0.00 0.24 0.06 0.88 1.12 0.06 28 10.428.96 2.12 12.01 9.44 6.60

The standard error was calculated to be 0.2318 for form (I) and 0.4128for form (II). Calibration models based on these averages were thendetermined.

1. Hydroxycarbonate(I) Calibration Model

The Rietveld hydroxycarbonate (I) response was done for the 28calibration standards spanning 0-30% hydroxycarbonate(I). Theroot-mean-square error of the uncalibrated Rietveld data is 1.52%. Theslope of the response curve is the sensitivity of the Rietveld responseper unit concentration (0.8127). This slope is subsequently used incalculating the minimum quantitation limit for hydroxycarbonate (I)determination.

The response data were used to generate a linear regression model forhydroxycarbonate (I) determination across the full calibration range.The predictive equation is:% Hydroxycarbonate(I)=1.2287×(Rietveld °HC(I))−0.456

The correlation coefficient for this model is 0.9986, and the predictedvalues from this model exhibit a root-mean-square error of 0.27%.

2. Hydroxycarbonate(II) Calibration Model

The Rietveld hydroxycarbonate(II) response for the 28 calibrationstandards spanned a concentration range of 0.9-31% hydroxycarbonate. Theroot-mean-square error of the uncalibrated Rietveld data is 1.54%. Theslope of this curve is the sensitivity of the Rietveld response per unitconcentration (0.8199). This slope is subsequently used in calculatingthe minimum quantitation limit for hydroxycarbonate (II) determination.

The response data were used to generate a linear regression model forhydroxycarbonate (II) determination across the full calibration range.The predictive equation is:% Hydroxycarbonate(II)=1.2143×(Rietveld % HC(II))−0.5353

The correlation coefficient for this model is 0.9955, and the predictedvalues from this model exhibit a root-mean-square error of 0.4861%.

F. Precision

Method precision was determined by the analysis of 9 lanthanum carbonatesamples that exhibit visually non-detectable response forhydroxycarbonate (I and II) and have varying concentrations ofLa₂(CO₃)₃.4H₂O. These were analyzed by the procedure outlinedhereinabove. This estimate of precision therefore encompassesuncertainty due to variations in:

-   -   (1) Sample matrix (samples represent multiple lots and various        storage conditions),    -   (2) Sample presentation (different sample holders and        autosampler positions used), and    -   (3) Data analysis (x-axis shifting and subsequent Rietveld        analysis).

The Rietveld responses and predicted analyte concentrations for thesamples used are used to calculate the 95% confidence intervals for theexperimental results. The standard deviations and 95% confidenceintervals for hydroxycarbonate (I and II) determination are summarizedbelow: Hydroxycarbonate (I) Hydroxycarbonate (II) Average −0.13% 0.02%Standard Deviation, σ 0.229% 0.091% 95% Confidence Interval 0.46% 0.18%G. Detection Limit

The detection limit (LOD) was established by calculating the upper 99%confidence limit of the response observed in the 9 samples visually freeof analyte. These values are: Average Predicted Concentration StandardDetection Analyte (Analyte-free Samples) Deviation Limit HC(I) −0.13%0.229% 0.55% HC(II) 0.02% 0.091% 0.29%H. Minimum Quantitation Limit

The minimum quantitation limit (MQL), expressed as 10(c/S), where ca isthe standard deviation of the response observed in the 9 samplesvisually free of analyte and S is the slope, i.e., the Rietveld responseover the true analyte content. Results are summarized below. StandardMinimum Analyte Deviation Slope Quantitation Limit HC(I) 0.229 0.81272.82% HC(II) 0.091 0.8199 1.11%I. Accuracy of the Validation Standards

Accuracy may be reported as percent recovery by the assay of the knownamount of analyte in the validation standard. Six validation standardswere prepared, with analyte concentrations ranging from 0.5 to 10% forHC(I) and 1.8 to 10.9% for HC(II). Octahydrate was allowed to vary from0.5 to 10%.

Recovery data for the validation standards for hydroxycarbonate (I) and(II), respectively are: Accuracy of Validation Standards Analyte ActualRange, % % Recovery (all data) HC(I) 4.3-10.1 90.4 ± 9.0 HC(II) 1.8-10.998.1 ± 6.4J. System Suitability

To evaluate system suitability, results obtained when the XRPD tubeintensity was significantly lowered were examined for accuracy. Lowerintensities were achieved experimentally by lowering the acceleratingvoltage from 40 kV to 20 kV. This resulted in a 74% reduction in tubeintensity. This sample was reliably predicted under these conditions(the average Rietveld % of HC(I) changed from 1.67% to 1.70% and theaverage Rietveld % of HC(II) changed from 3.13% to 3.17%). Thistherefore demonstrates system suitability.

K. Ruggedness

Two samples were analyzed by two different analysts, and one sample wasfurther analyzed on two different instruments. No bias between theoperators or instrument was observed. The results of % HC(I) and %HC(II) determinations are: Predicted Predicted Sample Analyst Instrument% HC(I) % HC(II) 1 A X 1.67 3.36 1 A X 1.51 3.31 1 B X 1.61 3.39 1 B X1.59 3.27 2 A X 9.87 11.27 2 A X 9.81 9.68 2 B X 10.15 10.89 2 B X 10.0310.25 2 B X 9.46 9.26 2 B Y 10.10 10.29 2 B Y 10.03 10.31L. Conclusion

This quantitative method is applicable for the determination oflanthanum hydroxycarbonate (I and II) in lanthanum carbonatetetrahydrate lanthanum carbonate samples. The method is preferred forsamples containing at least 68% of La₂(CO₃)₃ tetrahydrate. XRPD analysiscan reliably determine lanthanum hydroxycarbonate (I and II) inlanthanum carbonate lanthanum carbonate as summarized below: DetectionQuantitation Upper Analytical Analyte Limit (LOD) Limit (MQL) LimitHydroxycarbonate (I) 0.55% 2.82% 30% Hydroxycarbonate (II) 0.29% 1.11%31%

Example 6.4 XRD of Tablets Using Rietveld Analysis

This technique has been validated for lanthanum carbonate tablets aswell as powders. The tablets can be represented as % weight ofLHC/weight of ingoing lanthanum carbonate hydrate. Lanthanumhydroxycarbonate polymorph (I) and (II) limit of detection (LOD) and LOQfor the tablet by Rietveld analysis is provided as follows, with thenumber in parentheses corresponding to the equivalent percent of ingoinglanthanum carbonate hydrate. Detection Limit Quantitation Limit Analyte(LOD) (MQ L) Hydroxycarbonate (I) 0.65% (2.5%) 1.8% (6.8%)Hydroxycarbonate (II) 0.23% (0.9%) 2.0% (7.6%)

The present invention is not to be limited in scope by the specificembodiments described herein. Indeed, various modifications of theinvention in addition to those described herein will be apparent tothose skilled in the art from the foregoing description. Suchmodifications are intended to fall within the scope of the appendedclaims.

All references cited herein, including all patents, published patentapplications, and published scientific articles and books, areincorporated by reference in their entireties for all purposes.

1. A method of assaying the purity of a rare earth compound having atleast one known impurity, wherein at least one of the salt or impurityis a compound that disassociates in aqueous media, comprising: (i)obtaining an X-ray diffraction pattern of the salt; (ii) obtaining aplurality of reference samples containing the impurity or impurities;(iii) obtaining a plurality of X-ray diffraction patterns of thereference samples; and (iv) performing Rietveld analysis on the X-raydiffraction patterns to obtain: the detection limit, minimumquantitation limit (MQL), and/or upper analytical limit from thereference samples and the predicted impurity concentration value fromthe rare earth compound pattern.
 2. A method of assaying theconcentration of lanthanum hydroxycarbonate in a lanthanum carbonatecomposition comprising: (i) obtaining an X-ray diffraction pattern ofthe lanthanum carbonate; (ii) obtaining a plurality of reference samplescontaining the lanthanum hydroxycarbonate; (iii) obtaining a pluralityof X-ray diffraction patterns of the reference samples; and (iv)performing a Rietveld analysis on the X-ray diffraction patterns toobtain: the detection limit, minimum quantitation limit (MQL), and/orupper analytical limit from the reference samples and the predictedpercent of lanthanum hydroxycarbonate.
 3. The method of claim 1, furthercomprising: (v) classifying the predicted concentrations as: below thedetection limit, between the detection limit and the MQL, between theMQL and upper analytical limit, and greater than the upper analyticallimit; (vi) for samples having a predicted concentration between thedetection limit and the MQL, performing a visual analysis of the XRPDpatterns; and (ix) optionally reporting purity or impurity level.
 4. Themethod of claim 1, wherein both the rare earth compound and the impuritydisassociate in an aqueous media to the same measurable degradants. 6.The method of claim 1, wherein the rare earth compound is a lanthanumcarbonate, lactate, acetate, or citrate.
 7. The method of claim 6,wherein the lanthanum salt is La₂(CO₃)₃.xH₂O, wherein x has a value from0 to
 10. 8. The method of claim 7, wherein the impurity is La(CO₃)OH. 9.The method of claim 8, wherein the impurity is a combination ofLa(CO₃)OH form (I) and form (II).
 10. The method of claim 1, wherein theX-ray diffraction pattern from the lanthanum compound is obtained intriplicate.
 11. The method of claim 1, wherein X-ray diffractionpatterns are obtained for at least 5 reference samples.
 12. The methodof claim 11, wherein X-ray diffraction patterns are obtained for atleast 20 reference samples.
 13. The method of claim 1, wherein the X-raydiffraction pattern is obtained by a two theta continuous scan atapproximately 1°/min.
 14. The method of claim 1, further comprisingvisually determining if the impurity is present based on the presence ofX-ray diffraction peaks characteristic of the impurity.
 15. A method ofpreparing lanthanum carbonate comprising: (i) preparing a crudelanthanum carbonate; (ii) subjecting the crude lanthanum carbonate to apurity assay comprising the steps: (a) obtaining an X-ray diffractionpattern of the salt; (b) obtaining a plurality of reference samplescontaining the impurity or impurities; (c) obtaining a plurality ofX-ray diffraction patterns of the reference samples; and (d) performingRietveld analysis on the X-ray diffraction patterns to obtain: thedetection limit, minimum quantitation limit (MQL), and/or upperanalytical limit from the reference samples and the predicted impurityconcentration value from the rare earth compound pattern, (iii) when thelanthanum carbonate contains lanthanum hydroxycarbonate above the limitof detection according to the assay of (ii), purifying the lanthanumcarbonate and repeating step (ii).
 16. A pharmaceutical compositioncomprising lanthanum hydroxycarbonate form (I) characterized by an X-raypowder diffraction pattern having peaks at approximately 17.7°, 24.4°,and 30.3° two theta, wherein the lanthanum hydroxycarbonate content ofthe composition comprises at least 96% lanthanum hydroxycarbonate form(I).
 17. The pharmaceutical composition of claim 16, wherein thelanthanum hydroxycarbonate content of the composition comprises at least98% lanthanum hydroxycarbonate form (I).
 18. The pharmaceuticalcomposition of claim 17, wherein the lanthanum hydroxycarbonate contentof the composition comprises at least 99% lanthanum hydroxycarbonateform (I).